We offer three lines of evidence which together strongly imply that MHC class 1 proteins are the specific cell surface receptor of SV40: 1) SV40 specifically and competitively inhibits the binding of an anti-MHC 1 mAB to the cell surface; 2) pretreatment of cells with the anti-MHC 1 mAB blocks infection by SV40; and 3) exposure of MHC class 1- human lymphoblastoid cells to SV40 virions does not yield viral T antigen-producing cells whereas transfection with SV40 DNA does. To make the case compelling, we propose here to also show the following: 1) that the insertion and expression of the gene for MHC class 1 expression into the MHC class 1- cells renders them susceptible to infection by SV40; 2) that SV40 and MHC class 1 proteins can be co-immunoprecipitated from the cell surface; and 3) that incubation with purified soluble MHC class 1 protein inhibits SV40 infectivity. We will apply the same criteria to determine whether MHC class 1 proteins also serve as the receptor of the related polyomaviruses of humans, JCV and BKV. We will consider some possible consequences of MHC class 1 proteins serving as the SV40 receptor. We will determine whether the accumulation of progeny SV40 virions at the cell surface (our observation) might inhibit MHC-restricted CTL-mediated cell killing. We will also determine whether the recently reported preference of SV40 for the apical membrane domain of polarized epithelial cells correlates with a similar asymmetry in the distribution of class 1 MHC proteins. Finally, it was also reported that SV40 is preferentially released from the apical surface of polarized cells. We propose to determine if the targeted release of SV40 might involve, and be dependent upon, its interaction with intracellular MHC class 1 proteins.